The trimethyldiol stereopentad is a polypropionate sequence found in many medicinally active natural products. It is possible that the pair of hydrogen bond donors/acceptors in conjunction with the conformation-influencing characteristics of the methyl groups is responsible for recognition and binding of these materials at the active site of various biological targets. While the five-center stereopentad can exist in 32 stereoisomeric forms, it appears, based upon examination of the structure-searchable databases, that only 5 of these possibilities appear in natural products reported thus far. This number can be expanded to 10 by adding those compounds which bear a keto or an ethyl group at one of the alcohol or methyl positions, respectively.
The synthesis of biologically significant structures that incorporate polypropionate sequences has been the focal point of recent research efforts. The ever-increasing need for the preparation of chiral drugs as single enantiomers has fostered the evolution of methods of polypropionate segment synthesis including asymmetric aldol and asymmetric allyl metal additions to aldehydes.
All syntheses that target a single enantiomer ultimately must be related to one or more substances obtained from the chiral pool. It is recognized that syntheses that generate their asymmetry via a chiral catalyst are desirable because one molecule of catalyst is responsible for the creation of a multitude of new chiral progeny. For maximum effect, the chiral catalyst must be commercially available, deliver product in high yield, high ee, and exhibit high turnover numbers.
Multiply-convergent syntheses that combine stereochemically defined, functionality rich segments are often inefficient. Adoption of an easily scaled segment synthesis primarily impacts the probability of success of a synthetic project. Enantiopure segments prepared via catalytic processes have intrinsic advantages over stoichiometric use of enantiopure auxiliaries or reagents as these strategies are ‘high overhead,’ in that they generate added time and expense. Even successful syntheses that adopt the latter approach may be limited with respect to potential scale-up.
Cross-conjugated 6 and 7-membered dienyl sulfones have been developed and now comprise a collection of termini-differentiated acyclic arrays bearing 2-5 stereocenters. As illustrated in FIG. 1, scheme 1, Jacobsen asymmetric epoxidation of dienylsulfone of 2 with about 1% catalyst loading can give greater than 80% yields of epoxides RR-3 or SS-3 with greater than 97% ee. Reapplication of the catalytic Jacobsen epoxidation protocol to 5 effects greater than 12:1 double stereoselection, providing greater than 75% isolated crystalline yields of the individual members of the 6 and 7 family with 97% de (Scheme 1). Trimethylaluminum or dimethylcuprate undergoes complementary addition to silyl ether syn-7, giving alcohols 8 and 10, respectively. Alternatively, reaction of alcohol syn-6 with methyl lithium provided the α-methylated product 9α. While cleavage of the vinyl sulfones 8 and 10β gave the pseudoenantiomers (enantiomers with protecting group reversal) 11 and 12β, respectively, further evolution of these compounds in order to access polypropionates having C4,5 (arrows, scheme 1) functionalized would not be easily accomplished.
Accordingly, the need exists for improved stereospecific, efficient syntheses of sulfides and sulfones, including dienyl sulfides and sulfones. Novel enantiopure diastereomers made by such syntheses would also prove useful in a number of applications. For example, they could serve as bioactive agents, including pharmaceutical compositions which have stereochemical requirements. Such compounds could also be used as standards for determining the stereochemistry of segments of natural products and other compounds which are suspected of having set stereochemistries within their chemical structuces.